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e-Poster Display session

17P - Driving NK cell immunotherapy against NSCLC, in the context of hypoxia, using tri-specific engagers

Date

07 Mar 2022

Session

e-Poster Display session

Presenters

Jeffrey Miller

Citation

Annals of Oncology (2022) 33 (suppl_1): S9-S12. 10.1016/annonc/annonc839

Authors

J.S. Miller1, M. Felices2, D.A. Vallera3, B. Ettestad3, C. Hallstrom3, B. Kodal2, D.A. Todhunter3, U.S. Arvindam3, S.K. Phung3, Q. Kile3, G. Berk4, P.R. Kennedy3

Author affiliations

  • 1 Masonic Cancer Center - University of Minnesota, Minneapolis/US
  • 2 University of Minnesota, 55455 - Minneapolis/US
  • 3 University of Minnesota, Minneapolis/US
  • 4 GT Biopharma, 90212 - Beverly Hill/US
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Abstract 17P

Background

Mesothelin is a tumor-associated antigen overexpressed in several solid tumors, including lung adenocarcinoma. This antigen has been targeted in clinical trials in the form of drug conjugates and chimeric antigen receptors. However, both the hypoxic tumor microenvironment of solid tumors and impaired immune response in cancer patients present a challenge to successful immunotherapy. We hypothesized that a biologic that promotes immune cell survival and proliferation in addition to anti-cancer effects could overcome some of the challenges in treating mesothelin-expressing non-small cell lung cancer (NSCLC). Natural killer (NK) cells are innate immune cells that can kill tumor cells and release inflammatory cytokines that promote adaptive immune responses. In NSCLC, the number of NK cells circulating prior to treatment or infiltrating the tumor environment is predictive of clinical response.

Methods

For the treatment of NSCLC, we developed a tri-specific killer engager (TriKE®) that contains an IL-15 moiety, a humanized anti-CD16 single domain antibody, which binds the Fc gamma receptor on NK cells, and an anti-mesothelin single chain variable fragment. NK cells isolated from human blood were challenged with lung carcinoma lines in the presence of TriKE or single domain controls. Proliferation, cytokine production and cytotoxicity were assessed by flow cytometry and live cell imaging. Advanced incubators (Xcellbio) were used to vary the level of oxygen during culture from 1% (hypoxia) to 20% (normoxia).

Results

NSCLC lines are normally refractory to NK cell killing, but in the presence of this TriKE, NK cells from NSCLC patient blood collected at different stages of treatment were able to kill NSCLC cells and drive proliferation of the NK cells. Hypoxia impairs NK cell cytotoxicity, but when NK cells were exposed to hypoxia they killed NSCLC cells more effectively if TriKE was present during exposure and testing than if IL-15 was present alone.

Conclusions

This pre-clinical evidence suggests that a mesothelin-targeted TriKE can work alongside current standard of care in NSCLC patients and provide benefit even in the hypoxic environment of a solid tumor.

Legal entity responsible for the study

The authors.

Funding

NIH Research Grand and partial funding GT Biopharma.

Disclosure

J.S. Miller, M. Felices: Financial Interests, Personal and Institutional, Advisory Board: GT Biopharma; Financial Interests, Personal, Stocks/Shares: GT Biopharma; Financial Interests, Personal, Research Grant: GT Biopharma. D.A. Vallera: Financial Interests, Personal and Institutional, Advisory Board: GT Biopharma; Financial Interests, Personal, Licensing Fees: GT Biopharma; Financial Interests, Personal, Research Grant: GT Biopharma. G. Berk: Financial Interests, Personal and Institutional, Full or part-time Employment: GT Biopharma. All other authors have declared no conflicts of interest.

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